Search

Neuroblastoma is the most common and deadly childhood tumor. Relapsed or refractory neuroblastoma has a very poor prognosis despite recent treatment advances. To investigate genomic alterations associated with relapse and therapy resistance, whole-genome sequencing was performed on diagnostic and relapsed lesions together with constitutional DNA from seven children. Sequencing of relapsed tumors indicates somatic alterations in diverse genes, including those involved in RAS-MAPK signaling, promoting cell cycle progression or function in telomere maintenance and immortalization. Among recurrent alterations, CCND1-gain, TERT-rearrangements, and point mutations in POLR2A, CDK5RAP, and MUC16 were shown in ≥ 2 individuals. Our cohort contained examples of converging genomic alterations in primary-relapse tumor pairs, indicating dependencies related to specific genetic lesions. We also detected rare genetic germline variants in DNA repair genes (e.g., BARD1, BRCA2, CHEK2, and WRN) that might cooperate with somatically acquired variants in these patients with highly aggressive recurrent neuroblastoma. Our data indicate the importance of monitoring recurrent neuroblastoma through sequential genomic characterization and that new therapeutic approaches combining the targeting of MAPK signaling, cell cycle progression, and telomere activity are required for this challenging patient group.

Background: Specific knowledge is required in pediatric oncology, and specialization of nurses has been identified as a priority. In Sweden, a national program in pediatric oncology nursing has been offered since 2003. The aim of this study was to gain knowledge of nurses’ perceptions of the impact of this educational program. Methods: Eighty nurses who had completed the educational program in three cohorts (2012–2019) were invited to participate in this cross-sectional survey. An electronic study-specific questionnaire containing multiple-choice questions was used. Data were analyzed using descriptive statistics and correlation tests. Results: Fifty-nine (74%) nurses completed the survey, of whom 98% responded that they would recommend the program to a large/fairly large extent. At the time of the survey, 15 (25%) participants had left pediatric oncology care. Among the remaining 44, 31 (71%) of the nurses were working bedside, and 13 (42%) of these combined this with a special position (e.g., consultant nurse). The education resulted in career advancement, as the number of nurses with special positions increased following completion of the program, from 20% to 59%. The vast majority stated that the knowledge gained from the education contributed to increased confidence in interactions with the children/families. Discussion: Continuing education of nurses in pediatric oncology has an impact on career opportunities in clinical practice and contributes to nurses’ confidence and professional work. However, education is not enough to retain competent nurses. Employers need to be aware of the role of the work environment, aspects of work–life balance and career paths.

Background Sweden adopted a different strategy than many other countries to combat the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and kept most schools open. Initial reports from China suggested that coronavirus disease 2019 (COVID-19) was milder in children compared to adults, but there was a lack of data from immunocompromised children. Therefore, we investigated the rate of verified SARS-CoV-2 infections in our Swedish pediatric oncology patients. Procedure This was a multicenter retrospective study. A questionnaire including patient data as well as SARS-CoV-2 data was sent to the six Swedish childhood cancer centers in May 2021. Results During the first pandemic year, 49 patients were identified as SARS-CoV-2 positive, and 22 (45%) children were hospitalized with COVID-19. Two children needed intensive care, but no COVID-19-related deaths were reported. Most patients (n = 36, 73%) were on active chemotherapy treatment and 23 children (49%) attended school or daycare at least part-time. Half of the SARS-CoV-2-positive patients experienced a delay in cancer treatment. Conclusions Despite the rapid spread of SARS-CoV-2 in Sweden, without a strict lockdown of the society, the number of nationally reported pediatric oncology patients with polymerase chain reaction (PCR)-verified infection was low, and the majority of children had mild disease. Our data show that treatment interruptions occurred frequently and this should clearly be avoided for the coming years. Funding Agencies|Swedish Childhood Cancer Fund [KP2021-0034, 2020-0008]

PURPOSE Ewing 2008R3 was conducted in 12 countries and evaluated the effect of treosulfan and melphalan high-dose chemotherapy (TreoMel-HDT) followed by reinfusion of autologous hematopoietic stem cells on event-free survival (EFS) and overall survival in high-risk Ewing sarcoma (EWS). METHODS Phase III, open-label, prospective, multicenter, randomized controlled clinical trial. Eligible patients had disseminated EWS with metastases to bone and/or other sites, excluding patients with only pulmonary metastases. Patients received six cycles of vincristine, ifosfamide, doxorubicin, and etoposide induction and eight cycles of vincristine, actinomycin D, and cyclophosphamide consolidation therapy. Patients were randomly assigned to receive additional TreoMel-HDT or no further treatment (control). The random assignment was stratified by number of bone metastases (1, 2-5, and > 5). The one-sided adaptive-inverse-normal-4-stage-design was changed after the first interim analysis via Müller-Schäfer method. RESULTS Between 2009 and 2018, 109 patients were randomly assigned, and 55 received TreoMel-HDT. With a median follow-up of 3.3 years, there was no significant difference in EFS between TreoMel-HDT and control in the adaptive design (hazard ratio [HR] 0.85; 95% CI, 0.55 to 1.32, intention-to-treat). Three-year EFS was 20.9% (95% CI, 11.5 to 37.9) in TreoMel-HDT and 19.2% (95% CI, 10.8 to 34.4) in control patients. The results were similar in the per-protocol collective. Males treated with TreoMel-HDT had better EFS compared with controls: median 1.0 years (95% CI, 0.8 to 2.2) versus 0.6 years (95% CI, 0.5 to 0.9); P = .035; HR 0.52 (0.28 to 0.97). Patients age < 14 years benefited from TreoMel-HDT with a 3-years EFS of 39.3% (95% CI, 20.4 to 75.8%) versus 9% (95% CI, 2.4 to 34); P = .016; HR 0.40 (0.19 to 0.87). These effects were similar in the per-protocol collective. This observation is supported by comparable results from the nonrandomized trial EE99R3. CONCLUSION In patients with very high-risk EWS, additional TreoMel-HDT was of no benefit for the entire cohort of patients. TreoMel-HDT may be of benefit for children age < 14 years.

Background DNA repair deficiency disorders are rare inherited diseases arising from pathogenic (disease-causing) variants in genes involved in DNA repair. There are no standardized diagnostic assays for the investigation of pathological significance of unknown variants in DNA repair genes. We hypothesized that our assays for measuring in vitro patient blood cell hypersensitivity to DNA-damaging agents can be used to establish the pathological significance of unknown variants in DNA repair genes. Six patients with variants in the DNA repair genes PRKDC (two siblings), DCLRE1C (two siblings), NBN, and MSH6 were included. Here, we used the cell division assay (CDA) and the γ-H2AX assay, which were both developed and clinically validated by us, to measure patient cell hypersensitivity in response to ionizing radiation, mitomycin C, cytarabine and doxorubicin. Results Radiation hypersensitivity was detected in the two patients with variants in the PRKDC gene (p DCLRE1C variants (p p PRKDC variant were also deficient in removing γ-H2AX (p NBN gene were hypersensitive to mitomycin C (p = 0.0008) and deficient in both induction and removal of γ-H2AX in response to radiation. Conclusions The combination of the CDA and the γ-H2AX assay is useful in investigating the significance of unknown variants in some DNA repair genes.

The recently reported cell division assay (CDA) was optimized to measure the relative sensitivity of cells to cytotoxic drugs in vitro. Here, we investigated the in vitro hypersensitivity of lymphocytes from Fanconi anemia (FA) patients, to cytotoxic drugs using CDA. Peripheral blood mononuclear cells (PBMC) as well as cell lines derived from FA patients were treated with two DNA interstrand crosslinking (ICL) agents, mitomycin C and cyclophosphamide. Our data indicate that the CDA detects hypersensitivity of cells from FA patients to mitomycin C. Further, cell lines derived from FA‐patients were also hypersensitive to mitomycin C as well as cyclophosphamide, when assayed by the CDA. This study suggests that the CDA is a useful alternative for the diagnosis of FA patients' hypersensitivity to ICL agents.

Introduction Data regarding real-world impact on cancer clinical research during COVID-19 are scarce. We analysed the impact of the COVID-19 pandemic on the conduct of paediatric cancer phase I-II trials in Europe through the experience of the Innovative Therapies for Children with Cancer (ITCC). Methods A survey was sent to all ITCC-accredited Early-Phase Clinical Trial Hospitals including questions about impact on staff activities, recruitment, patient care, supply of investigational products and legal aspects, between 1/March and 30/April/2020. Results Thirty-one out of 53 hospitals from 12 countries participated. Challenges reported included staff constraints (30% drop), reduction in planned monitoring activity (67% drop of site initiation visits and 64% of monitoring visits) and patient recruitment (61% drop compared to 2019). The percentage of phase I, phase II trials and molecular platforms closing to recruitment in at least one site was 48.5%, 61.3% and 64.3%, respectively. Additionally, 26% of sites had restrictions on performing trial assessments due to local contingency plans. Almost half of the units suffered impact upon pending contracts. Most hospitals (65%) are planning on improving organizational and structural changes. Conclusion The study reveals a profound disruption of paediatric cancer early phase clinical research due to the COVID-19 pandemic across Europe. Reported difficulties affected both patient care and monitoring activity. Efforts should be made to reallocate resources to avoid lost opportunities for patients and to allow the continued advancement of oncology research. Identified adaptations to clinical trial procedures may be integrated to increase preparedness of clinical research to futures crises., Highlights • The COVID-19 pandemic has profoundly disrupted paediatric cancer clinical research. • A drastic drop in recruitment in phase I/II trials compared to 2019 was observed. • Current research needs reorganization to avoid loss of opportunities for children.

The ATM kinase is a central component of the DNA damage repair machinery and redox balance. ATM dysfunction results in the multisystem disease ataxia-telangiectasia (AT). A major cause of mortality in AT is respiratory bacterial infections. Whether ATM deficiency causes innate immune defects that might contribute to bacterial infections is not known. Here we have shown that loss of ATM impairs inflammasome-dependent anti-bacterial innate immunity. Cells from AT patients or Atm(-/-) mice exhibited diminished interleukin-1β (IL-1β) production in response to bacteria. In vivo, Atm(-/-) mice were more susceptible to pulmonary S. pneumoniae infection in a manner consistent with inflammasome defects. Our data indicate that such defects were due to oxidative inhibition of inflammasome complex assembly. This study reveals an unanticipated function of reactive oxygen species (ROS) in negative regulation of inflammasomes and proposes a theory for the notable susceptibility of AT patients to pulmonary bacterial infection.

BACKGROUND The nucleosomal histone protein H2AX is specifically phosphorylated (γ-H2AX) adjacent to DNA double-strand breaks (DSBs) and is used for quantifying DSBs. Many chemotherapies and ionizing radiation (IR) used in cancer treatment result in DSBs. Therefore, γ-H2AX has a significant potential as a biomarker in evaluating patient sensitivity and responsiveness to IR and chemotherapy. METHODS Here, we report a flow cytometry-based quantification of γ-H2AX (FCM-γ-H2AX assay) customized for clinical practice. RESULTS We validated that our method is able to detect DNA damage in peripheral blood mononuclear cells (PBMCs) treated with DSB inducing agents. The method also detected the DNA repair deficiency in PBMCs treated with DNA repair inhibitors, as well as the deficiency in DNA repair signaling in PBMCs from two ataxia telangiectasia patients. CONCLUSIONS The FCM-γ-H2AX assay has sufficient analytical sensitivity and precision to measure levels of DNA damage and DNA repair for clinical purposes. © 2016 International Clinical Cytometry Society.

Objectives The clonogenic assay examines cell sensitivity to toxic agents and has been shown to correlate with normal tissue sensitivity to radiotherapy in cancer patients. The clonogenic assay is not clinically applicable due to its intra-individual variability and the time frame of the protocol. We aimed to develop a clinically applicable assay that correlated with the clonogenic assay. Design and methods We have developed a faster and less labor-intensive cell division assay (CD assay) using flow cytometry and incorporation of a fluorescent thymidine analogue. The CD assay was calibrated to the clonogenic assay and optimized for peripheral blood lymphocytes. Results Following ionizing radiation of primary human skin fibroblasts, the four-day CD assay gave similar results as the 14-day clonogenic survival assay. In lymphocytes isolated from patient blood samples, the CD assay was able to detect increased radiosensitivity in ataxia telangiectasia patients and increased radiosensitivity after in vitro treatment with DNA-PK and ATM inhibitors. The CD assay found a variation in the intrinsic radiosensitivity of lymphocytes isolated from healthy control samples. The CD assay was able to measure the anti-proliferation effect of different chemotherapeutic drugs in lymphocytes. Conclusions Our results indicate that the CD assay is a fast and reliable method to measure the anti-proliferation effect of DNA-damaging agents with a potential to find the most sensitive patients in the work-up before cancer treatment.

Congenital dyserythropoietic anemia type II, a recessive disorder of erythroid differentiation, is due to mutations in SEC23B, a component of the core trafficking machinery COPII. In no case homozygosity or compound heterozygosity for nonsense mutation(s) was found. This study represents the first description of molecular mechanisms underlying SEC23B hypomorphic genotypes by the analysis of five novel mutations. Our findings suggest that reduction of SEC23B gene expression is not associated with CDA II severe clinical presentation; conversely, the combination of a hypomorphic allele with one functionally altered results in more severe phenotypes. We propose a mechanism of compensation SEC23A-mediated which justifies these observations.

We describe two children with significant bleeding: one with multiple ecchymoses and the other with scrotal bleeding. In both patients, the activated partial thromboplastin time (APTT) was prolonged, with positivity for lupus anticoagulants (LA). However, the Owren prothrombin time (PT), usually insensitive for LA, was also prolonged. The presence of LA is associated with diverse clinical manifestations, with most patients being asymptomatic while others present venous or arterial thrombosis. Bleeding in conjunction with LA is rare and it is unusual to see prolongation of the Owren PT assay due to LA. An extended laboratory investigation of one of the patient's plasma revealed not only LA but also a specific nonphospholipid-dependent antiprothrombin antibody causing an acquired hypoprothrombinemia. Conclusion: It is likely that the low prothrombin activity and not the LA caused the bleeding. The bleeding signs and symptoms in both patients subsided when the PT was normalized, although the prolonged APTT and the LA remained.

Background. Immunoreconstitution following childhood acute lymphoblastic leukemia (ALL) is a complex process during which various immune functions recover differentially. This process is difficult to elucidate since variables are interrelated and require simultaneous evaluation, rendering conventional statistical methods inappropriate. Procedure. We used principal components analysis (PCA) and projection of latent structures (PLS) to evaluate immune competence in 32 children treated for ALL. One or 6 months after completion of therapy, the relation between lymphocyte subpopulations, lymphocyte function and response to vaccination with tetanus, diphtheria and hemophilus influenzae, was investigated. Results. PCA demonstrated that increasing treatment intensity correlated with progressive immune dysfunction. Children treated with

Aim: Solid tumours constitute 40% of childhood malignancies. The Swedish Childhood Cancer Registry is population based and includes all children with cancer reported from the six paediatric oncolo ...

The nucleosomal histone protein H2AX is specifically phosphorylated (γ-H2AX) adjacent to DNA double-strand breaks (DSBs) and is used for quantifying DSBs. Many chemotherapies and ionizing radiation (IR) used in cancer treatment result in DSBs. Therefore, γ-H2AX has a significant potential as a biomarker in evaluating patient sensitivity and responsiveness to IR and chemotherapy.Here, we report a flow cytometry-based quantification of γ-H2AX (FCM-γ-H2AX assay) customized for clinical practice.We validated that our method is able to detect DNA damage in peripheral blood mononuclear cells (PBMCs) treated with DSB inducing agents. The method also detected the DNA repair deficiency in PBMCs treated with DNA repair inhibitors, as well as the deficiency in DNA repair signaling in PBMCs from two ataxia telangiectasia patients.The FCM-γ-H2AX assay has sufficient analytical sensitivity and precision to measure levels of DNA damage and DNA repair for clinical purposes. © 2016 International Clinical Cytometry Society.

The objective of this study was to examine the incidence and characteristics of Ara-C-related fever and the frequency and severity of infections after single-drug, high-dose Ara-C treatment (HDAC) in children treated for acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL). A retrospective review was performed of 169 courses of HDAC administered to 57 patients (age 1.8-17.8 years). Procalcitonin values (PCT) were analyzed in a subgroup of 16 patients. Fever during HDAC occurred in 113 of 169 (67%) cases. C-reactive protein (CRP) was elevated in the febrile patients (median 38 mg/L [range 3-150]). PCT was elevated (>0.5 ng/mL) during HDAC in 4 of the 16 evaluated patients. Corticosteroids could inhibit fever (P < 0.001). Myelosuppression after HDAC was prominent: 99% developed neutropenia (

Objective The aim was to examine the immune reconstitution after current chemotherapy for childhood ALL, with a special focus on finding immunologic variables that predict a poor immune response to vaccinations. Procedure In a cross-sectional study of 31 children after treatment with the NOPHO ALL-1992 protocol peripheral blood lymphocyte subsets, T- and B-cell function in vitro and serum immunoglobulins (Ig) were measured. All patients were examined once, at 1 or at 6 months after cessation of chemotherapy, immediately before vaccination with DT and Hib. Results Lymphocytes, T-cells, and CD4+ T-cells were low at 6 months after treatment. Naive T-cell subsets were more reduced than memory subsets. In the high risk (HR) ALL group, CD8+ T-cells were reduced at 6 months. NK-cells were low at 1 month, but normal at 6 months; however, the CD3+CD56+ (NKT) subset was reduced at both time points. Total B-cell number was low at 1 month, but normal at 6 months. A relative increase of CD5+ B-cells (B-1 cells) was evident, particularly in the HR group. Antigen-independent T- and B-cell function in vitro were affected at 1 month, but virtually normalized at 6 months. Serum IgM level was decreased at 1 month and IgG3 level was increased at 1 and 6 months. Conclusions This study shows that immune reconstitution after childhood ALL is slower than previously reported and emphasizes the influence of treatment intensity. The most intensively treated patients still have persistent abnormalities in T-, B-, and NK-cell subsets at 6 months post therapy and show a poor response to immunization with T-cell dependent antigens. In the HR group, routine re-immunizations before this time point are of limited benefit, and the effect of repeated vaccinations should be evaluated. © 2004 Wiley-Liss, Inc.

Objectives Immunity to diphtheria toxoid (D), tetanus toxoid (T), and Haemophilus influenzae type b (Hib) is affected in children with acute lymphoblastic leukemia (ALL). The aims were to examine immunity and to compare the response to immunization at 1 or 6 months after treatment. Methods Thirty-one patients were immunized with DT and conjugated Hib vaccine (ActHib) at 1 month or 6 months after treatment of ALL with the NOPHO 92 protocol. Antibody levels were determined before and 3 weeks after vaccination. Specific T and Hib antibody-secreting cells of IgG/IgA/IgM isotypes were analyzed in peripheral blood using an ELISPOT technique. Results All specific antibody levels decreased during ALL treatment, and protective levels after treatment were noted for 17% against D, 33% against T, and 100% against Hib. No high-risk patient had full D or T protection after treatment. After vaccination all the standard- and intermediate-risk patients achieved full protection against D, T, and Hib. The high-risk group showed insufficient immune response (full protection after vaccination: D 56%, T 22%, Hib 78%). No difference was found between vaccination at 1 month or 6 months after treatment. The poor antibody production in the high-risk group correlated to low numbers of antibody-secreting cells. Conclusions Nonprotective antibody levels against D, T, and Hib after childhood ALL are more common than previously thought. Insufficient immune response was restricted to the high-risk group and was related to a low number of memory B cells in this study. Immunizations should be included in follow-up after childhood ALL, and the policy should be adapted to treatment intensity.

UNLABELLED This study examined whether the initial plasma levels of tumour necrosis factor alpha (TNFalpha) and interferon gamma (IFNgamma) in 131 children with newly diagnosed cancer were associated with haematopoietic suppression, and whether plasma levels of TNFalpha or haemoglobin at diagnosis affects long-term prognosis in childhood acute lymphoblastic leukaemia (ALL). CONCLUSIONS IFNgamma, and possibly also TNFalpha, were related to anaemia in children with solid tumours. Neither TNFalpha levels nor Hb levels were associated with increased risk of ALL relapse.

Solid tumours constitute 40% of childhood malignancies. The Swedish Childhood Cancer Registry is population based and includes all children with cancer reported from the six paediatric oncology centres in Sweden. The aim was to investigate incidence and survival.We used the new WHO ICCC-3 for reclassification of the patients. Incidence and survival analyses were performed in the study population.Two thousand four hundred and eighty-seven children (15 years) were diagnosed with solid tumours in Sweden between 1983 and 2007. The distribution of diagnoses was similar to that reported in other studies. The annual incidence was 65.3 per million children. The survival rates at 10 years of follow-up have improved significantly when comparing the two time periods, 1983-1995 and 1995-2007 (76 vs. 82%; p0.01).The mean annual incidence of solid tumours in children was 65.3/million and has been stable during the study period. Survival rates for solid tumours at 5, 10 and 20 years follow-up were 80, 79 and 76%, respectively.

Immunoreconstitution following childhood acute lymphoblastic leukemia (ALL) is a complex process during which various immune functions recover differentially. This process is difficult to elucidate since variables are interrelated and require simultaneous evaluation, rendering conventional statistical methods inappropriate.We used principal components analysis (PCA) and projection of latent structures (PLS) to evaluate immune competence in 32 children treated for ALL. One or 6 months after completion of therapy, the relation between lymphocyte subpopulations, lymphocyte function and response to vaccination with tetanus, diphtheria and hemophilus influenzae, was investigated.PCA demonstrated that increasing treatment intensity correlated with progressive immune dysfunction. Children treated with high intensity had poor response to vaccination associated with loss of humoral memory, decreased CD4(+) 45RA(+) T-lymphocytes and increased CD5+ B-lymphocytes. Patients treated with intermediate intensity had better preservation of humoral memory but decreased CD4(+) 45RA(+) T-cells. Patients with a low intensity regimen had similar vaccination response and lymphocyte levels as controls.Our findings demonstrate the utility of PCA and PLS in detecting hidden structures in complex data and suggest that, even 6 months after therapy, patients treated with intermediate and high intensity have attenuated responses to de novo antigens whereas those with high intensity also respond poorly to recall antigens.

This study examined whether the initial plasma levels of tumour necrosis factor alpha (TNFalpha) and interferon gamma (IFNgamma) in 131 children with newly diagnosed cancer were associated with haematopoietic suppression, and whether plasma levels of TNFalpha or haemoglobin at diagnosis affects long-term prognosis in childhood acute lymphoblastic leukaemia (ALL).IFNgamma, and possibly also TNFalpha, were related to anaemia in children with solid tumours. Neither TNFalpha levels nor Hb levels were associated with increased risk of ALL relapse.

Background Treatment with high-dose cytarabine (1-β-D-arabinofuranosylcytosine) is often associated with an acute febrile reaction sometimes including abdominal pain, myalgia, and rash. The similarity of these symptoms to those caused by hypersecretion of cytokines in the systemic inflammatory response syndrome (SIRS) prompted us to investigate the plasma levels of proinflammatory cytokines during treatment of children with high-dose cytarabine. Procedure Sixteen children treated for hematological malignancies and in clinical remission were studied during treatment with six infusions of cytarabine given every 12 hr at a dose of 2 g/m2. Blood samples for analysis of tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-1γ (IL-1γ), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10) and interleukin-1 receptor antagonist (IL-1ra) were obtained prior to treatment and subsequently at 12, 36 and 60 hr. Additional samples were collected as soon as fever occurred. Results Thirteen of 16 patients developed fever at a median time of 30 hr following start of treatment. At 12 hr levels of TNF-α were elevated followed by a rise in IL-6, IFN-α, and IL-1ra, peaking at the onset of fever. Thereafter these levels slowly declined whereas low IL-10 levels became detectable. Conclusions We conclude that high-dose cytarabine treatment often induces release of TNF-α followed by the sequential release of other proinflammatory cytokines. Most likely these cytokines mediate the development of symptoms comprising the cytarabine syndrome. Med Pediatr Oncol 2001;37:459–464. © 2001 Wiley-Liss, Inc.

Chng (2003) indicated fever as an important part of the cytarabine syndrome and suggests cytokines as mediators. In an attempt to investigate the mechanisms behind cytarabine-induced fever, we evaluated 16 children (1AE5– 14AE8 years old) in clinical remission during high–dose cytarabine treatment (six infusions of 2 g/m 2 every 12 h). Fever (median 38AE5� C, range 38AE0–39AE7� C) occurred in 13 of 16 patients at a median of 28 h (20–47 h) after the start of the first infusion. The fever declined spontaneously in 10 of 13 patients despite continued infusions. The series of infusions was not interrupted in any case. Some patients showed signs of malaise, abdominal pain, myalgias and self-limiting rash, but none was severely ill. Blood cultures were negative and no antibiotics were administered. C-reactive protein was low at the beginning of treatment, but increased at 36 h to 21AE 5+6 AE6 mg/l [mean + standard error of the mean (SEM); P

SummaryDysfunction in Ataxia-telangiectasia mutated (ATM), a central component of the DNA repair machinery, results in Ataxia Telangiectasia (AT), a cancer-prone disease with a variety of inflammatory manifestations. By analyzing AT patient samples and Atm−/− mice, we found that unrepaired DNA lesions induce type I interferons (IFNs), resulting in enhanced anti-viral and anti-bacterial responses in Atm−/− mice. Priming of the type I interferon system by DNA damage involved release of DNA into the cytoplasm where it activated the cytosolic DNA sensing STING-mediated pathway, which in turn enhanced responses to innate stimuli by activating the expression of Toll-like receptors, RIG-I-like receptors, cytoplasmic DNA sensors, and their downstream signaling partners. This study provides a potential explanation for the inflammatory phenotype of AT patients and establishes damaged DNA as a cell intrinsic danger signal that primes the innate immune system for a rapid and amplified response to microbial and environmental threats.